Pharmacologically active compounds

ABSTRACT

The compounds are N-(heterocyclomethylthioalkyl)derivatives of alkylguanidines, C-alkyl and C-aryl amidines and S-alkylisothioureas. The compounds may also have N&#39;-lower alkyl or N&#39;-(heterocyclomethylthioalkyl)substituents. Three compounds of the invention are S-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]isothiourea, N,N&#39;-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]acetamidine, N,N&#39;-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]N&#34;-methylguanidine. The compounds of this invention are histamine H 2  -antagonists.

This is a division of application Ser. No. 551,220 filed Feb. 19, 1975,now U.S. Pat. No. 4,036,971.

This invention relates to pharmacologically active compounds, topharmaceutical compositions containing these compounds and to methods ofblocking histamine H₂ -receptors by administering these compounds. Thecompounds of the invention can exist as acid addition salts but, forconvenience, reference will be made throughout this specification to thepresent compound.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine is a typical example, anddiphenhydramine and chlorpheniramine are other examples, are mediatedthrough histamine H₁ -receptors (Ash and Schild, Brit. J. Pharmac.Chemother, 27, 427, (1966)). However, other of the biological actions ofhistamine are not inhibited by "antihistamines" and actions of this typewhich are inhibited by a compound described by Black et al. (Nature,236, 385 (1972)) and called burimamide are mediated through receptorswhich are defined by Black et al. as histamine H₂ -receptors. Thushistamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure; in thetreatment of certain conditions, for example inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ -antagonists is useful. The compounds of thisinvention are histamine H₂ -antagonists. These compounds are representedby the following formula ##STR1##

FORMULA I

wherein R₁ represents a grouping of the structure shown in Formula II:

    het -- CH.sub.2 -- S -- (CH.sub.2).sub.n --

FORMULA II

wherein Het is a nitrogen containing 5 to 6 membered heterocyclic ringselected from imidazole, pyridine, thiazole, isothiazole, thiadiazole,isoxazole and triazole which is optionally substituted by lower alkyl,hydroxyl, halogen or amino: n is 2 or 3: R₂ is lower alkyl, phenyloptionally substituted by hydroxy or mercapto, SR₄ or, when R₃ is otherthan hydrogen, NHR₅ : R₃ is hydrogen, lower alkyl or R₁ : R₄ and R₅which may be the same or different are lower alkyl: and R₃ may be linkedwith R₄ or R₅ to form an additional 5-membered ring such as thiazolineor imidazoline, or a pharmaceutically acceptable acid addition salt.Throughout the present specification and claims, by the term "loweralkyl" we mean an alkyl group containing from 1 to 4 carbon atoms,preferably methyl. It will be understood that the structure illustratedin Formula I is only one of several representations and that othertautomeric forms are also covered by the present invention.

In a preferred group of compounds n is 2 and it is particularlypreferably that Het is imidazole, optionally substituted by methyl orhalogen; thiazole; or isothiazole or pyridine optionally substituted bymethyl, hydroxyl or halogen. Halogen is preferably chloro or bromo.

Useful series of compounds are a) that wherein R₃ is identical to R₁, b)that wherein R₂ is lower alkylamino and c) that wherein R₂ is loweralkylthio. Examples of specific compounds falling within the scope ofthe present invention are:

S-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-isothiourea

N,n'-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]acetamidine

N,n'-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]N"-methylguanidine.

The compounds of Formula I wherein R₂ is SR₄ and R₄ does not form anadditional 5-membered ring may be prepared by alkylation of a thioureaof Formula III: ##STR2##

FORMULA III

wherein R₁ and R₃ are as defined in Formula I to give an isothiourea ofFormula IV ##STR3##

FORMULA IV

wherein R₄ is lower alkyl. This reaction may be carried out convenientlyusing hydrogen chloride and the alcohol R₄ OH, preferably at an elevatedtemperature near to the boiling point of the alcohol R₄ OH.Alternatively the thiourea of Formula III may be alkylated using analkyl halide, such as methyl iodide, or an alkylsulphate such as diethylsulphate.

The compounds of Formula I other than those wherein R₂ is loweralkylthio may be prepared by treatment of a compound of Formula V.##STR4##

FORMULA V

wherein R₃ is as defined in Formula I, R₆ is R₂ or NHR₁, R₁ and R₂ beingas defined in Formula I except that R₄ when present is linked to R₃ toform a 5-membered ring such as a thiazoline ring, A is lower alkyl and Xis oxygen when R₆ is lower alkyl or phenyl optionally substituted byhydroxy or mercapto, and X is sulphur when R₆ is SR₄, NHR₅, or NHR₁,with an amine of formula R₇ NH₂, R₇ being R₁ when R₆ is R₂, and R₇ beinglower alkyl when R₆ is R₁ NH and R₃ is other than hydrogen.

Examples of particular processes falling within the above generalprocess are:-

(a) The preparation of compounds of Formula VI ##STR5##

FORMULA VI

wherein R₁, is as defined in Formula I,R₃ is lower alkyl or R₁ in whichcase the groups R₁ may be the same or different, and R₅ is lower alkyland R₃ may be linked to R₅ to form a 5-membered ring, by treatment of anisothiourea of Formula IV wherein R₃ is R₁ with either a loweralkylamine or an amine of formula R₁ NH₂.

(b) The preparation of compounds of Formula I, wherein R₂ is SR₄ and R₃and R₄ are linked to form a 5-membered ring, by the reaction of R₁ NH₂with an S-lower alkylthiazoline of formula VII: ##STR6##

FORMULA VII

wherein A represents a lower alkyl group.

(c) The preparation of compounds of Formula I wherein R₂ is lower alkylor phenyl optionally subsituted by hydroxy or mercapto by reaction of anamine of formula R₁ NH₂ with an iminoether of Formula VIII: ##STR7##

FORMULA VIII

wherein A represents a lower alkyl group.

The iminoethers of Formula VIII wherein R₃ is hydrogen may be preparedby the reaction between a nitrile of formula R₂ CN and a lower alkanolAOH. The iminoethers of Formula VIII wherein R₃ is R₁ are generated bythe reaction of an amine R₁ NH₂ with an orthoester of formula R₂-C-(OA)₃. Alternatively the compounds of Formula I wherein R₂ ismercaptophenyl may be prepared by treating the correspondinghydroxybenzamidine with phosphorus pentasulphide in a solvent such aspyridine. The compounds of Formula 1 block histamine H₂ -receptors, thatis they inhibit the biological actions of histamine which are notinhibited by "antihistamines" such as mepyramine but are inhibited byburimamide. For example, the compounds of this invention have been foundto inhibit histamine-stimulated secretion of gastric acid from thelumen-perfused stomachs of rats anaesthetized with urethane, at doses offrom 0.5 to 256 micromoles per kilogram intravenously. This procedure isreferred to in the above mentioned paper of Ash and Schild. The activityof these compounds as histamine H₂ -antagonists is also demonstrated bytheir ability to inhibit other actions of histamine which, according tothe above mentioned paper of Ash and Schild, are not mediated byhistamine H₁ -receptors. For example, they inhibit the actions ofhistamine on the isolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food.

In addition, the compounds of this invention show antiinflammatoryactivity in conventional tests such as the rat paw oedema test, wherethe oedema is induced by an irritant, the rat paw volume is reduced bysubcutaneous injection of doses of a compound of Formula I. In aconventional test, such as the measurement of blood pressure in theanaesthetised cat, the action of the compounds of this invention ininhibiting the vasodilator action of histamine can also be demonstrated.The level of activity of the compounds of this invention is illustratedby the effective dose producing 50% inhibition of gastric acid secretionin the anaesthetized rat and the dose producing 50% inhibition ofhistamine-induce tachycardia in the isolated guinea pig atrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier thereof. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to block histamine H₂ -receptors. The route ofadministration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regiment will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration, for example, as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingexamples wherein all temperatures are given in degrees Centigrade:-

EXAMPLE 1S-Methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-isothioureahydriodide

A mixture of N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea(2.29 g) and methyl iodide (1.56 g) in acetone (45 ml) containingmethanol (5 ml) was left at room temperature for 18 hours. Concentrationfollowed by recrystallisation from isopropyl alcohol-petroleum ether(b.p. 60/80°) gave the little compound (2.3 g) m.p. 128°-131°.

(Found: C, 28.8; H, 4.5; N, 14.8; S, 17.5; I, 33.8; C₉ H₁₆ N₄ S₂requires: C, 29.0; H, 4.6; N, 15.1; S, 17.2; I, 34.1%).

EXAMPLE 2N,S-Dimethyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-isothioureadihydriodide

N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (10.0g) was dissolved in methanol (400 ml) and 55% aqueous hydriodic acid(12.2 ml) was added, followed by methyl iodide (5.3 ml). The solutionwas heated under reflux for 4 hours and concentrated. The residue wasdissolved in methanol (100 ml) and ether was added to afford the titleproduct as the dihydriodide (5.48 g) m.p. 185°-186° (from isopropylalcohol).

(Found: C, 23.4; H, 3.9; N, 10.9; I, 49.6; S, 12.6; C₁₀ H₁₈ N₄ S₂.2HIrequires: C, 23.4; H, 3.9; N, 10.9; I, 49.4 S, 12.5%).

EXAMPLE 3 2-[2-(4-Imidazolylmethylthio)ethyl]amino-2-thiazolinehydriodide

A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole (from thedihydrobromide (5.0 g) and excess potassium carbonate) and2-methylthio-2-thiazoline hyriodide (4.09 g) in ethanol (100 ml) washeated under reflux for 21 hours. Following concentration the residuewas crystallised from methanolether and then recrystallised from ethanolto give the title compound (2.9 g) m.p. 148.5°-150.5°.

(Found: C, 29.0; H, 4.0; N, 15.0; S, 17.5; I, 34.0; C₉ H₁₄ N₄ S₂.HIrequires: C, 29.2; H, 4.1; N, 15.1; S, 17.5; I, 34.3%).

EXAMPLE 4 N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]benzamidinedihydrochloride

A solution of ethyl benzimidate hydrochloride (10.84 g) in water (25 ml)was basified with potassium carbonate (8.07 g) and extracted withdiethyl ester (3 × 30 ml). The ethereal extracts were combined and driedover anhydrous potassium carbonate. The potassium carbonate was removedby filtration and the filtrate concentrated to about 30 ml. To thelatter was added a solution of4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole (5.00 g) in ethanol.The combined solutions were allowed to stand at room temperature for 6days. The solution was concentrated to give an oil, cooled and acidifiedwith ethanolic hydrogen chloride. The solution was concentrated and theresidue crystallised from isopropanol (with a trace of ether) to giveN-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-benzamidine dihydrochloride(7.64 g) m.p. 221°-222.5° (from ethanol-ether).

(Found: C, 48.0; H, 5.9; N, 15.8; S, 9.1; C₁₄ H₁₈ N₄ S.2HCl requires: C,48.4; H, 5.8; N, 16.1; S, 9.2%)

EXAMPLE 5N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidinedihydrochloride.

4-Cyanophenol (11.91 g) was dissolved in dry diethyl ether (200 ml).Ethanol (10 ml) was added and the solution saturated with dry hydrogenchloride at 10°. The solution was stored at 0° over weekend. Yellowcrystals of ethyl 4-hydroxybenzimidate hydrochloride (4.425 g)deposited. A solution of ethyl 4-hydroxybenzimidate hydrochloride (4.425g) in water (10 ml) was basified with potassium carbonate (10.0 g) andextracted with diethyl ether (3 × 30 ml). This solution was dried overanhydrous potassium carbonate and added to a solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole in dry ethanol (100 ml).Over 7 days at room temperature a crystalline solid was deposited. Thecrude base was recrystallised from ethanol-ether to giveN-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidine as theethanolate (2.12 g) m.p. 136°-138°. A sample of the ethanolate (1.58 g)was converted to the dihydrochloride by the addition of ethanolichydrogen chloride. The solution was concentrated and the resulting solidrecrystallised to giveN-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidinehydrochloride (1.28 g) (225.5°-228°)

(Found: C, 46.3; H, 5.6; N, 15.2; S, 8.8; Cl, 19.4; C₁₄ H₁₈ N₄ OS.2HClrequires: C, 46.3; H, 5.6; N, 15.4; S, 8.8; Cl, 19.5%).

EXAMPLE 6 N,N'-bis-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]acetamidinetrihydrochloride

A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.00 g),triethyl orthoacetate (1.42 g) and acetic acid (0.525 g) was refluxedfor 60 minutes. The reaction mixture was allowed to cool, concentratedand dissolved in water. The aqueous solution was added to a solution ofpicric acid in boiling isopropanol. On cooling the crystalline picrateformed. This was recrystallised from isopropanol-water (3:1, 400 ml) togive N,N'-bis[2-(5-methyl-4-imidazolylmethylthio)ethyl]acetamidinetripicrate (5.95 g) m.p. 205°-206°. The tripicrate was converted to thetrihydrochloride by the addition of 5N hydrochloric acid (50 ml)followed by extraction with toluene (5 × 30 ml). The aqueous solutionwas concentrated and the residual solid was boiled with isopropanol andgradually crystallised. The crude trihydrochloride was recrystallisedfrom ethanol-ethyl acetate to giveN,N'-bis-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]acetamidinetrihydrochloride (1.89 g) m.p. 230°-232°.

(Found: C, 40.4; H, 6.2; N, 17.5; S, 13.2; Cl, 21.9. C₁₆ H₂₆ N₆ S₂. 3HCl requires: C, 40.4; H, 6.1; N, 17.7; S, 13.5; Cl, 22.4%).

In a similar manner

(a) N,N'-bis-[2-(3-bromo-2-pyridylmethylthio)-ethyl]acetamidine may beprepared from 3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine

(b) N,N'-bis-[2-(2-thiazolylmethylthio)ethyl]-acetamidine may beprepared from 2-[(2-aminoethyl)thiomethyl]-thiazole

(c) N,N'-bis-[2-(3-isothiazolylmethylthio)-ethyl]acetamidine may beprepared from 3[(2-aminoethyl)thiomethyl)-isothiazole.

(d) N,N'-bis-[2-(3-chloro-2-pyridylmethylthio)-ethyl]acetamidine, may beprepared from 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine.

EXAMPLE 72-[2-((5-Methyl-4-imidazolyl)methylthio)ethyl]amino-2-imidazolinodihydrochloride

A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (8.55 g)and 2-methylmercapto-2-imidazoline hydriodide (13.2 g) in ethanol (50ml) was heated under reflux for 15 hours. The residue followingconcentration was dissolved in ethanol and treated with sodium picratein hot ethanol. The picrate obtained on cooling was recrystallised fromethanol (16.5 g, m.p. 190°-192°) and treated with hydrochloric acid.Picric acid was removed by toluene extraction and the aqueous layer wasconcentrated and the residue recrystallised twice from isopropyl alcoholto give the title compound as the dihydrochloride (7.0 g) m.p.189°-191°.

(Found: C, 38.6; H, 6.3; N, 22.3; S, 10.5; Cl, 22.6 C₁₀ H₁₇ N₅ S.2HClrequires: C, 38.5; H, 6.1; N, 22.4; S, 10.3; Cl, 22.7%).

EXAMPLE 8N,N'-Dimethyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-guanidinedihydrochloride

N,N'S-Trimethylisothiouronium iodide (12.0 g) was converted into thesulphate by ion exchange on a resin in the SO₄.sup.═ form (IRA 401). Theconcentrated eluate of the sulphate was reacted directly with4-methyl-5-((2-aminoethyl)thiomethyl)-imidazole (6.85 g) at 70°-80° for48 hours. Following concentration, the crude product was converted to apicrate (8 g, m.p. 110°-120° (from aqueous ethanol)). Followingconversion to the hydrochloride and purification on an ion-exchangecolumn (OH⁻ form) with elution by hydrochloric acid, the title compound,m.p. 260° (dec) was obtained.

EXAMPLE 9S-Methyl-N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-iosthioureatrihydrochloride

(i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl) imidazole (34.0g) and carbon disulphide (7.6 g) in ethanol (250 ml) was heated underreflux for 6 hours. Concentration followed by chromatographicpurification of the product on a column of silica gel with elution byisopropyl alcohol-ethyl acetate followed by isopropyl alcohol-ethanolgave N,N'-bis[2-(5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (18 g),m.p. 133°-135°.

(Found: C, 47.0; H, 6.1; N, 22.0. C₁₅ H₂₄ N₆ S₃ requires: C, 46.8; H,6.3; N, 21.9%)

(ii) Dry hydrogen choride was passed into a solution ofN,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (7.7 g)in methanol at 80° for 5 hours. Concentration and re-evaporation withisopropyl alcohol affordedS-methyl-N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-isothioureatrihydrochloride (9.0 g), m.p. 212°-215° (isopropyl alcohol).

(Found: C, 37.6; H, 5.7; N, 16.3; S, 18.6; Cl, 20.5 C₁₆ H₂₆ N₆ S₃. 3 HClrequires: C, 37.8; H, 5.8; N, 16.5; S, 18.9; Cl, 20.9%).

EXAMPLE 10N,N'-bis-[2-((5-Methyl-4-imidazolyl)methylthio)ethyl]-N"-methylguanidine

A solution ofN,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio-ethyl]-S-methylisothioureatrihydrochloride (2.0 g) in 33% ethanolic methylamine (60 ml) was heatedunder reflux for 3 hours. The mixture was basified with sodiummethoxide, filtered and the filtrate was concentrated under reducedpressure. Treatment of the residue with ethanolic picric acid affordedN,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-N"-methylguanidinetripicrate (2.8 g) m.p. 169°-170°.

(Found: C, 38.0; H, 3.4; N, 20.7; S, 6.0. C₁₆ H₂₇ N₇ S₂.3 C₆ H₃ N₃ O₇requires: C, 38.2; H, 3.4; N, 21.0; S, 6.0%).

Treatment of the tripicrate with hydrochloric acid and removal of picricacid by extraction with toluene afforded the trihyrochloride.

In a similar mannerN,N'-bis-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-N"-butylguanidinemay be prepared using butylamine in ethanol in place of ethanolicmethylamine.

EXAMPLE 11N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-4-mercaptobenzamidine

(a) 4-Cyanothiophenol was treated with hydrogen chloride in ether at 0°and the hydrochloride salt produced was treated with potassium carbonateto give ethyl 4-mercaptobenzimidate. Ethyl 4-mercaptobenzimidate wastreated with 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole in dryethanol at room temperature to give the title product.

(b) N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidineand a slight excess of phosphorus pentasulphide were refluxed inpyridine for 45 minutes to give the title compound.

EXAMPLE 12 N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]acetamidine

A mixture of ethyl acetimidate and4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole in ethanol was allowedto stand at room temperature for 6 days. The mixture was concentrated,treated with ethanolic hydrogen chloride and evaporated to give thetitle product as the dihydrochloride.

EXAMPLE 13

Treatment of the following thioureas:

a.N-[2-(2-Pyriylmethylthio)ethyl]-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea.

b.N-[2-(3-Pyridylmethythio)ethyl]-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea.

c. N,N'-bis[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]thiourea.

d. N,N'-bis-[2-(3-isoxazolylmethylthio)ethyl]thiourea.

with hydrogen chloride in methanol according to the general procedure ofExample 9 (ii) results in the formation of the S-methylisothioureas:

a.S-Methyl-N-[2-(2-pyridylmethylthio)ethyl]-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]isothiourea.

b.S-Methyl-N-[2-(3-pyridylmethylthio)ethyl[-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]isothiourea.

c.S-Methyl-N,N'-bis-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]isothiourea.

d. S-Methyl-N,N'-bis-[2-((3-isoxazolylmethylthio)ethyl]-isothiourea.

and treatment of these S-methylisothioureas with methylamine accordingto the general procedure of Example 10 results in the formation of theN"-methylguanidines:-

a.N-[2-(2-pyridylmethylthio)ethyl]-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-N"-methylguanidine.

b.N-[2-(3-pyridylmethylthio)ethyl]-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-N"-methylguanidine.

c.N,N'-bis-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]N"-methylguanidine.

d. N,N'-bis-[2-(3-isoxazolyl-methylthio)ethyl]N"-methylguanidine.

EXAMPLE 14

Substitution of:

(a) 4-[(2-aminoethyl)thiomethyl]imidazole.

(b) 4-bromo-5-[(2-aminoethyl)thiomethyl]-imidazole.

(c) 1-methyl-2-[(2-aminoethyl)thiomethyl]-imidazole.

(d) 2-[(2-aminoethyl)thiomethyl]imidazole.

(e) 3-chloro-2-[(2-aminoethyl)thiomethyl]-pyridine.

(f) 3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine.

(g) 3-methyl-2-[(2-aminoethyl)thiomethyl]-pyridine.

(h) 2-[(2-aminoethyl)thiomethyl]thiazole.

(i) 3-[(2-aminoethyl)thiomethyl]isothiazole.

(j) 5-amino-2-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole.

(k) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole.

(l) 4-[(3-(2-aminomethyl)thiopropyl]imidazole.

for 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole in the generalprocedure of Example 9(i) followed by treatment of the product accordingto the general procedure of Examples 9(ii) results in the formation ofthe following S-methyl isothioureas.

a. S-methyl-N,N'-bis-[2-(4-imidazolyl methylthio)ethyl]-isothiourea.

b. S-methyl-N,N'-bis-[2-(5-bromo-4-imidazolylmethylthio)ethyl]-isothiourea.

c. S-Methyl-N,N'-bis-[2-(1-methyl-2-imidazolylmethylthio)ethyl]-isothiourea.

d. S-Methyl-N,N'-bis-[2-(2-imidazolyl methylthio)ethyl]-isothiourea.

e. S-Methyl-N,N'-bis-[2-(3-chloro-2-pyridylmethylthio)ethyl]-isothiourea.

f. S-Methyl-N,N'-bis[2-(3-bromo-2-pyridyl methylthio)ethyl]-isothiourea.

g. S-Methyl-N,N'-bis-[2-(3-methyl-2-pyridylmethylthio)ethyl]-isothiourea.

h. S-Methyl-N,N'-bis-[2-(2-thiazolyl methylthio)ethyl]-isothiourea.

i. S-Methyl-N,N'-bis-[2-(3-isothiazolyl methylthio)ethyl]-isothiourea.

j.S-Methyl-N,N'-bis-[2-(5-amino-2-(1,3,4-thiadiazolyl)-methylthio)ethyl]isothiourea.

k.S-Methyl-N,N'-bis-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]-isothiourea.

l. S-Methyl-N,N'-bis-[3-(4-imidazolylmethylthio)propyl]-isothiourea.

and treatment of these S-methyl isothioureas with methylamine accordingto the general procedure of Example 10 results in the formation of thefollowing N"-methylguanidines:

a. N,N'-bis-[2-(4-imidazolyl methylthio)ethyl]-N"-methylguanidine.

b. N,N'-bis-[2-(5-bromo-4-imidazolylmethylthio)ethyl]-N"-methylguanidine.

c. N,N'-bis-[2-(1-methyl-2-imidazolylmethylthio)ethyl]-N"-methylguanidine.

d. N,N'-bis-[2-(2-imidazolyl methylthio)ethyl]-N"-methyl-guanidine.

e. N,N'-bis-[2-(3-chloro-2-pyridyl methylthio)ethyl]-N"-methylguanidine.

f. N,N'-bis-[2-(3-bromo-2-pyridyl methylthio)ethyl]-N"-methylguanidine.

g. N,N'-bis-[2-(3-methyl-2-pyridyl methylthio)ethyl]-N"-methylguanidine.

h. N,N'-bis-[2-(2-thiazolyl methylthio)ethyl]-N"-methyl-guanidine.

i. N,N'-bis-[2-(3-isothiazolyl methylthio)ethyl]-N"-methyl-guanidine.

j.N,N'-bis-[2-(5-amino-2-(1,3,4-thiazolyl)methylthio)ethyl]-N"-methylguanidine.

k. N,N'-bis-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]-N"-methylguanidine.

l. N,N'-bis-[3-(4-imidazolylmethylthio)propyl]-N"-methylguanidine.

                  EXAMPLE 15                                                      ______________________________________                                        Ingredients             Amounts                                               ______________________________________                                        N,N'-bis-[2-(5-methyl-4-imidazolyl-                                           methylthio)ethyl]N"-methylguanidine                                                                     150    mg                                           trihydrochloride.                                                             Sucrose                   75     mg                                           Starch                    25     mg                                           Talc                      5      mg                                           Stearic Acid              2      mg                                           ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

                  EXAMPLE 16                                                      ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N,N'-bis-[2-(5-methyl-4-imidazolyl-                                           methylthio)ethyl]-N"-methylguanidine                                          trihydrochloride.         200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

What is claimed is:
 1. A compound of the formula: ##STR8## wherein R₁represents a grouping of the structure

    Het -- CH.sub.2 -- S -- (CH.sub.2).sub.n --

wherein Het is imidazole which is attached at a ring carbon and which isoptionally substituted by lower alkyl or halogen; n is 2 or 3; R₂ is SR₄; R₃ is hydrogen, lower alkyl or R₁ ; and R₄ is lower alkyl, or apharmaceutically acceptable addition salt thereof.
 2. A compoundaccording to claim 1 wherein n is
 2. pg,25
 3. A compound according toclaim 1 wherein Het is imidazole, optionally substituted by methyl orhalogen.
 4. A compound according to claim 1 wherein R₃ is identical toR₁.
 5. A compound according to claim 1, said compound beingS-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)ethyl] isothiourea.
 6. Apharmaceutical composition to block histamine H₂ -receptors, saidhistamine H₂ -receptors being those histamine receptors which are notblocked by mepyramine but are blocked by burimamide, comprising, in aneffective amount to block said histamine H₂ -receptors, a compound ofclaim 1 in combination with a pharmaceutically acceptable diluent orcarrier.
 7. A method of blocking histamine H₂ -receptors, said histamineH₂ -receptors being those histamine receptors which are not blocked bymepyramine but are blocked by burimamide, which comprises administeringto an animal in need of blocking of said histamine H₂ -receptors in aneffective amount to block said histamine H₂ -receptors a compound ofclaim 1.